TOPIC:IONTOPHORESIS-

SONOPHORETIC SYSTEM

S U B M I T T E D B Y : C H A I T R A L I G I J A R E

Subject: NOVEL DRUG DELIEVERY SYSTEM

2PH801

CONTENTS

Introduction

• Iontophoretic drug delivery system

• Sonophoretic drug delivery system

• Iontophoretic Vs sonophoretic drug delivery system

• Reference

INTRODUCTION

THE SKIN-

Protective layer with large no. of dead cells, hence acts as barrier to

penetration. The skin accounts for about 15% of adult’s wt.

Penetration varies with humidity, pigmentation, age, chemical status of all

layers.

Stratum Corneum (SC) offers maximum resistance. SC consists of

keratinocytes and lipid bilayer.

Permeability can be increased by Chemicals, Electrical Fields or

Ultrasound which disrupt lipid bilayer of SC and increase permeability.

IONTOPHORETIC DRUG DELEIVERY SYSTEM

Iontophoresis can be defined as the permeation of ionized drug molecules

across biological membranes under the influence of electrical current.

Principles of Iontophoresis :

Electrode placement is dependent on the electric charge of the ion which is to

be delivered into the tissue.

A positive ion will be delivered from the positive electrode and a negative ion

will be delivered by the negative electrode.

Electrical energy assists the movement of ions across the stratum corneum

according to the basic electrical principle “like charges repel each other and

opposite charges attract each other.”

ADVANTAGES OF IONTOPHORESIS

1) Virtually painless when properly applied.

2) Provides option for patients unable to receive injections.

3) Reduced risk of infection due to non-invasive nature.

4) Medications delivered directly to the treatment site.

5) Minimizes potential for tissue trauma from an injection.

6) Treatments are completed in minutes.

DRAWBACK

1) Excessive current density usually results in pain.

2) Burns are caused by electrolyte changes within the tissues.

3) The high current density and time of application would generate extreme

pH, resulting in a chemical burn.

4) This change in pH may cause the sweat duct plugging perhaps precipitate

protein in the ducts.

5) Electric shocks may cause by high current density at the skin surface.

6) Ionic form of drug in sufficient concentration is necessary for iontophoretic

delivery.

IONTOPHORETIC DRUG DELIVERY SYSTEM WORKS

BY THREE MECHANISM

(a) Ion-electric field interaction provides an additional force that drives ions

through the skin.

(b) The flow of electric current increases the permeability of the skin.

(c) Electro-osmosis produces bulk motion of solvent that carries ions or

neutral species with the solvent stream. Electro-osmotic flow occurs in a

variety of membranes and is in the same direction as the flow of counter-

ions. It may assist or hinder drug transport.

COMPONENTS

1. Power source for generating controlled direct current.

2. Electrodes that contain and disperse the drug.

3. Negatively or positively charged aqueous medication.

4. A localized treatment site

MOVEMENT OF IONS IN SOLUTION

Ionization- Soluble compounds dissolve into ions suspended in solutions that

are called electrolytes.

Electrophoresis- Movement of ions in solution according to the electrically

charged currents acting on them.

Cathode = Negatively charged electrode

i. Highest concentration of electrons

ii. Repels negatively charged ions

iii. Attracts positively charged ions

iv. Accumulation of positively charged ions in a small area creates an alkaline

reaction.

CONTD…

Anode = Positively charged electrode

i. Lower concentration of electrons

ii. Repels positively charged ions

iii. Attracts negatively charged ions

iv. Accumulation of negatively charged ions in a small area creates an acidic

reaction

Positively charged ions are driven into tissues from positive pole

Negatively charged ions are driven into tissues from negative pole

Knowing correct ion polarity is essential.

CONTD…

Force which acts to move ions through the tissues is determined by

i. Strength of the electrical field

ii. Electrical impedance of tissues to current flow.

Strength of the electrical field is determined by the current density

i. Difference in current density between the active (Active electrode- the one being

used to drive the ion into the tissue)and inactive electrodes establishes a gradient

of potential difference which produces ion migration within the electrical field.

Current density may be altered by

i. Increasing or decreasing current intensity

ii. Changing the size of the electrode:Increasing the size of the electrode will

decrease current density under that electrode.

CONTD…

Current density should be reduced at the cathode

i. Alkaline reaction is more likely to produce tissue damage than acidic

reaction.

ii. Thus negative electrode should be larger to reduce current density.

Higher current intensities necessary to create ion movement in areas where

skin and fat layers are thick further increasing chance of burns around

negative electrode

Sweat ducts are primary paths by which ions move through the skin and act to

decrease impedance facilitating the flow of direct current as well as ions.

The quantity of ions transferred into the tissues through iontophoresis is directly

proportional to

i. Current density at the active electrode

ii. Duration of the current flow

iii. Concentration of ions in solution

Once the ions pass through skin they recombine with existing ions and free

radicals in the blood thus forming the necessary new compounds for

favorable therapeutic interactions .

IONTOPHORESIS GENERATOR

Produce continuous direct current in the order as per the

requirement.

Assures unidirectional flow of ions.

It also consist of a timer for regulating the supply of current. 11

Intensity control:

1 to 5 mA

Constant voltage output that adjusts to normal variations in tissue

impedance thus reducing the likelihood of burns.

Automatic shutdown if skin impedance reduces to preset limit.

Adjustable Timer for giving the duration of treatment.

ELECTRODES OF IONTOPHORESIS

Active pad- This electrode have a small chamber covered by a semipermeable

membrane into which ionized solution may be injected.

Dispersive pad- Also known as Inactive pad. Dispersive pad should be larger

than active pad to reduce the current density leading to reduction of

irritation.

The polarity of these electrode depends on the characterictics of drugs and

these electrodes self adheres to the skin .

Electrodes Material

The electrode materials used for iontophoretic delivery are to be harmless to

the body and sufficiently flexible to apply closely to the body surface.

The most common electrodes used for iontophoretic drug delivery are :

1. Aluminum foil

2. Platinum and

3. Silver/Silverchloride

A better choice of electrode is silver/silver chloride because it minimizes

electrolysis of water during drug delivery.

Electrode Preparation

To ensure maximum contact of electrodes skin should be

shaved and cleaned prior to attachment of the electrodes.

Do not excessively abrade skin during cleaning since

damaged skin has lowered resistance to current and a burn

might occur more easily.

Attach self-adhering active electrode to skin.

Inject ionized solution into the chamber.

Attach self-adhering inactive electrode to the skin and attach

lead wires from generator to each.

Electrode Placement

• Size and shape of electrodes can cause variation in current

density (smaller = higher density)

• Inactive electrodes should be separated by a distance atleast

the diameter of active electrode

FACTORS AFFECTING IONTOPHORETIC DRUG

DELEIVERY SYSTEM

Operational factor

1) Composition of the formulation

Concentration of the drug

solution

pH of the donor solution

Ionic strength

Presence of co-ions

2) Physicochemical properties

Molecular size

Polarity

Charge

Molecular weight

3) Experimental conditions

current density

polarity of electrodes

electrode material

4) Biological factors

Intra and inter variability

Regional blood flow

Skin pH

Condition of skin

IONTOPHORESIS FORMULATION

Solvent

• Water

Co-solvent

• PEG

• glycerol

• Ethanol

• PG

Matrix

• Hydrophillic

• Nonionizing polymer

Drug salt

• Halide salt

Counter reservoir

• Weak acid

• Weak base

Iontotrophic patch

SONOPHORETIC DRUG DELIEVERY SYSTEM

Sonophoresis, is a process that exponentially increases the absorption of

topical compounds (transdermal delivery) with high-frequency ultrasound.

Sonophoresis occurs because ultrasound waves stimulate micro-vibrations

within the skin epidermis and increase the overall kinetic energy of

molecules making up topical agents.

It is thought that high-frequency ultrasound can influence the integrity of the

stratum corneum and thus affect its penetrability.

Among the agents examined are

hydrocortisone,

lidocaine,

salicylic acid

ADVANTAGES

1) Avoids vagaries associated with gastrointestinal absorption due to pH,

enzymatic activity, drug-food interactions etc.

2) Substitute oral administration when the route is unsuitable as in case of

vomiting, diarrhea.

3) Avoids hepatic “first pass” effect.

4) Avoids the risks and inconveniences of parenteral therapy.

5) Reduces daily dosing, thus, improving patient compliance.

6) Extends the activity of drugs having short plasma half-life through the

reservoir of drug present in the therapeutic delivery system and its

controlled release characteristics.

7) Rapid termination of drug effect by removal of drug application from the

surface of the skin.

8) Rapid identification of the medication in emergencies. (e.g.. Non-

responsive, unconscious, or comatose patient.

CONTD…

9) Elimination of the hazards and difficulties of I.V. infusions or I.M.

injections.

10) Enhance therapeutic efficacy, reduced side effects due to optimization of

the blood concentration-time profile and elimination of pulse entry of drugs

into the systemic circulation.

11) Provide predictable activity over extended duration of time and ability to

approximate zero-order kinetics.

12) Improved control of the concentrations of drug with small therapeutic

indices.

13) Minimize inter and intrapatient variation.

14) Suitability for self-administration.

LIMITATIONS

1) Only limited number of potent drugs can be absorbed in therapeutic dose.

2) Many systemically effective therapeutic drugs produce skin irritation.

3) The drug must have some desirable physicochemical properties for

penetration through stratum corneum.

4) If the drug dosage required for therapeutic value is more than 10mg/day,

the transdermal delivery will be very difficult.

5) The barrier function of the skin changes from one site to another on the

same person, from person to person and with age.

UNDERSTANDING THE DRUG DELIVERY

Sonophoresisor ultrasound can be used to

create holes in the skin for fluids to

travel into or out of the skin. By emitting

sound at a particular frequency, the

sound waves disrupt the lipid-bilayer of

the stratus corneum (outermost layer of

skin which has the most barrier

properties), creating more and larger

microchannels in the skin. Drugs can be

administered through these channels .

GENERATION OF ULTRASOUND

Ultrasound is a sound wave possessing frequencies above 20 kHz .

These waves are characterized by two main parameters, frequency and

amplitude.

The waves used for sonophoresis which reduce the resistance offered by SC

lie in the frequency range of 20 KHz to 20 MHz.

Ultrasound is generated with the help of a device called sonicator which is a

AC electric signal generator. It produces a AC electric signal which is applied

across a piezoelectric crystal i.e. transducer.

The crystal undergoes rhythmic deformation due to electric current, producing

ultrasonic vibrations.

In the process of ultrasonic wave generation, electric energy is converted into

mechanical energy in the form of oscillations, which generates acoustic

waves.

Ultrasound is applied by bringing the transducer in contact with the skin.

For sonophoretic delivery, the desired drug is dissolved in a solvent and applied

to the skin.

The coupling medium can be the same as the solvent used to dissolve the

drug or it can be a commercial ultrasound coupling e.g. gel.

It helps to match impedence of tissue with the impedence of the transducer, so

that the Ultrasound gets properly into the tissue.

SELECTION OF ULTRASOUND PARAMETERS

(1) Ultrasound frequency :

a) Therapeutic Frequency Ultrasound (1-3 MHz)

b) Low Frequency Ultrasound (Below 1MHz)

c) High Frequency Ultrasound (Above 3MHz)

(2) Ultrasound intensity:

Various ultrasound intensities in the range of 0.1 to 2 W/cm2

(3) Pulse length:

Ultrasound can be applied in a continuous or pulse mode. The pulse mode is

frequently used because it reduces severity of side effects such as thermal

effects.

It was also found that urea permeability of cuprophane membrane increased

from 6 to 56% as pulse length increased from 100 to 400 ms.

VARIOUS TYPES OF MECHANISM FOR

SONOPHORESIS

Although considerable attention has been given to the investigation

of sonophoresis in the past years, its mechanisms were not clearly

understood, reflecting the fact that several phenomena may occur in the

skin upon ultrasound exposure. These include:

1) Cavitation (generation and oscillation of gas bubbLes).

2) Thermal effects (temperature increase).

3) Induction of convective transport.

4) Mechanical effects (occurrence of stresses due to pressure variation

induced by ultrasound.)

CAVITATION EFFECTS:

Cavitation is the formation of gaseous cavities in a medium ultrasound

exposure. The primary cause for cavitation is ultrasound -induced pressure

variation in the medium . It is further of 2 types

1. Inertial cavitation: The rapid growth and collapse of a bubble.

2. Stable cavitation: The slow oscillatory motion of a bubble in an ultrasound

field.

Collapse of cavitation bubbles releases a shock wave that can cause structural

alteration in the surrounding tissue. The cavitational effects vary inversely

with ultrasound frequency and directly with ultrasound intensity

At higher frequencies it becomes difficult to generate cavitation due to

the fact that the time between the positive and negative acoustic pressures

becomes too short, diminishing the ability of dissolved gas within the

medium to diffuse into the cavitation nuclei . For example, application of

ultrasound at 20 kHz induced transdermal transport enhancements of up to

FIGURE: CAVITATIONAL EFFECT

Thermal effects

Ultrasound does not pass through tissues with 100% efficiency. During its

propagation, the ultrasound wave is partially scattered and absorbed by

the tissue medium, resulting in attenuation of the emitted wave. The lost

energy is converted into heat, while the remainder of the wave

penetrates into and propagates through the medium

Convective transport

Fluid velocities are generated in porous medium exposed to ultrasound

due to interference of the incident and reflected ultrasound waves in the

diffusion cell and oscillations of the cavitation bubbles. Experimental findings

suggest that convective transport does not play an important role in the

observed transdermal enhancement.

Mechanical effects

Ultrasound is a longitudinal pressure wave inducing sinusoidal pressure

variations in the skin, which, in turn, induce sinusoidal density variation. At

frequencies greater than 1 MHz, the density variations occur so rapidly

that a small gaseous nucleus cannot grow and cavitational effect cease.

But other effects due to density variations, such As generation of cyclic

stresses because of density changes that ultimately lead to fatigue of the

medium, may continue to occur. Lipid bilayers, being self-assembled

structures, can easily be disordered by ese stresses, which result in an

increase in the bilayer permeability. This increase is, however, non-significant

and hence mechanical effects do not play an important role in therapeutic

sonophoresis. Thus, cavitation induced lipid bilayer disordering is found to

be the most important cause for ultrasonic enhancement of transdermal

transport.

DEPENDENCE OF SONOPHORETIC SKIN

PERMEABILISATION ON

ULTRASOUND

Frequency: Attenuation of an acoustic wave is inversely proportional to

its frequency, and thus as the frequency increases, the ultrasound

penetrates less deeply into the skin. Low-frequency ultrasound(f~20

kHz) is significantly more potent in enhancing skin permeability

compared to therapeutic ultrasound (f~1-3 MHz)

Intensity: The skin conductivity increases with increasing intensity,

but upto a certain point, and then drops off. This is due to the increase

in the total energy put into the system with increasing ultrasound

intensity. The linearity between skin conductivity and ultrasound

intensity may break down at higher intensities (>15 W/cm2 ) due to

other effects such as ‘acoustic decoupling’ which is a phenomena

where cavitation generated near the ultrasound source results in

the formation of large number of gaseous cavities, thus reducing the

amount of energy delivered to the system. The intensity is directly

dependent on the acoustic energy emitted and the speed of sound in the

medium.

Mode: Ultrasound can be applied in continuous or pulsed (sequential)

mode. The rise in temperature is faster and more intense with the

continuous mode.

Threshold energy: Skin conductivity enhancement is directly

proportional to the incident ultrasound energy density. There exists a

threshold ultrasound energy below which the effect of ultrasound on skin

conductivity cannot be detected, and beyond the threshold value the

conductivity increases with the energy density.

VARIATION IN ENHANCEMENT OF SONOPHORESIS FOR

VARIOUS DRUGS

The observed enhancement for a particular drug depends significantly

on the physicochemical and pharmacokinetic properties of the

permeant, and hence varies from drug to drug. Another factor

of great importance in the selection of drugs is their biological half-

life; the lower the half-life, the faster the rate at which steady state

levels in blood are attained. The sonophoretic enhancement of

transdermal drug transport can be quantitatively predicted based

on knowledge of two physiochemical properties of the drug:

passive skin permeability, and octanol–water partition coefficient, K

o/w.

MARKETED PRODUCTS

Microlysis:

The Microlysis developed by Ekos is designed to deliver ultrasound

and thrombolytic (clot-dissolving) drug directly into the area of a brain

clot. The Microlysis device is a miniature catheter that is inserted into

an artery in the brain until it reaches the clot. Drug is infused through

the catheter to the tip, where a tiny ultrasound transmitter is located.

The ultrasound and drug are designed to be administered

simultaneously because it has been shown that ultrasound energy

induces a temporary change in the structure of a clot that allows

the drug to penetrate more efficiently into the inner reaches of

the blockage.

• SonoPrep:

Sontra Medical Corporation is the pioneer of SonoPrep, a

non-invasive and painless ultrasonic skin permeation

technology. The medical device uses an ultrasonic method

to make skin temporarily more permeable. The small,

battery-powered device applies a low-frequency, ultrasonic

energy to the skin for 15 seconds. The sound waves open small

cavities in the skin by disorganizing the lipid bi-layer, creating

tiny, reversible channels

through which fluids can be extracted and delivered. The

skin goes back to its normal state within 24 hours. Sontra

is investigating the delivery of several large proteins and

peptides by incorporating the use of the SonoPrep device

in combination with transdermal patches to deliver the drug

transdermally. Sontra Medical is also developing a vaccine

against dengue fever .

Sonoderm Technology: The sonoderm is a device based on the

generation of low frequency ultrasounds waves acting on a

vibratory and thermal way, this technology is called

ultrasonotherapy. ImaRx is now developing Sonolysis in which MRX-

801 microbubbles and ultrasound waves are used to disperse the

blood clots and restore blood flow.

Patch-Cap and U-strip: In June 2005, Dermisonics obtained the patent for

the ultrasonic Patch-Cap and a flexible patch for transdermal

delivery of drugs via ultrasound.The U-Strip is a drug delivery

system .

USES OF SONOPHORESIS

Sonophoresis also used in treatment of glaucoma and corneal infection,

to increase the permeability of drugs.

Ultrasound can also be used for nail delivery of drugs.

Ultrasound helps in treatment of wide varieties of sports injuries such as tennis

elbow, tendon problems, repairing damaged ligaments, muscle spasms,

stiff joints, fractured bones and cartilage. Also used in healing of

wounds, skin rejuvenation, nerve stimulation, and improving the strength

and elasticity of scar tissues

Sonophoresis is used in the treatment of damaged skin.

Process of cavitation takes place during the treatment but the cavities

disappear after the treatment and histological examination has shown

that the skin is normal after treatment.

Hormone delivery.

Low-frequency ultrasonic gene delivery.

Ultrasound is used for Calcific Tendinitis of the s.houlder

DRUG USED BY SONOPHORESIS

1) Sonophoresis with Corticosteroid:

Majority of studies on sonophoresis, ultrasound was used to enhanced the delivery

of steroidal anti-inflammatory drugs (e.g. hydrocortisone. Ultrasound could carry

hydrocortisone across a vascular membrane for the effective treatment of

polyarthritis

Also, hydrocortisone sonophoresis is useful in the treatment of numerous musculo-

skeletal injuries.

2) Sonophoresis with Salicylates:

In combination with ultrasound, Salicylate could be moved into deeper, subdermal

tissues to help to reduce pain.

3) Sonophoresis with Anesthetics:

The effectiveness of sonophoresis has been explored extensively for

delivery of local anesthetics. Sonophoresis with Decadron and Lidocaine

results in relief from their trigger point pain.

4) Sonophoresis with other Drugs:

Ultrasound as an enhancer of benzydamine hydrochloride (3%) a

nonsteroidal anti-inflammatory drug.

Sonophoresis of D- mannitol, a diuretic.

Ultrasound with topically applied Amphotericin B.

SONOPHORETIC VS. IONTOPHORETIC DRUG

DELIVERY SYSTEM

Sonophoresis Iontophoresis

Sonophoresis is the enhancement of

migration of drug molecules by ultrasonic

energy.

Iontophoresis is movement of ions

of soluble salts across a membrane through the

skin under an externally applied potential

difference

Sonophoresis uses acoustic energy

(ultrasound) to drive molecules into tissues.

Iontophoresis uses electiral current to transport

ions into tissues

Proper choice of ultrasound parameters

including ultrasound energy dose, frequency,

intensity, pulse length and distance of

transducer from the skin, is critical for for

efficient sonophoresis.

Proper choice of electricity parameters including

Current density, Current profile, Duration of

treatment, Electrode material, Polarity of

electrodesis critical for efficient Iontophoresis.

Sonophoresis usually employs a ultrasound

between 20 KHz to 20 MHz

Iontophoresis usually employs a direct current

between 0.5 mA to 5.0 mA

In sonophoresis drugs mixing with a

coupling agent like gel, cream,

ointment.

In Iontophoresis drug is mix with

solvent .

The main mechanism for transport of

drug is “Cavitation”

The main mechanism for transport of

drug is “Electroporation”

Drug should be in aqueous or non

aqueous and ionized or non in ionized

form.

Drug must be in aqueous and must be

ionized form.

Enhanced partitioning, Lipid bilayer

disordering, Keratin denaturation etc

gives the the synergetic effect of

sonophoresis

Electrophoresis, Lipid bilayer

disordering, Electroosmosis etc. Gives

synergetic effect of Iontophoresis .

Ultrasound can be applied in a Electrical current can be applied only

CONTD….

REFERENCES

• N.K.Jain, Sonophoresis: Biophysical of Transdermal Drug Delivery,

Controlled and Novel Drug Delivery, 1 st edition, 1997, page. 208-235

• James Swarbrick, Transdermal Delivery: Sonophoresis, Encyclopedia of

pharmaceutical technology, 3 rd edition, Volume-6, 2007, page no. 3828-

3842

• Mr. Ashish Pahade, Dr. Mrs. V.M.Jadhav, Dr. Mr. V.J.Kadam, Sonophoresis:

an overview, International Journal of Pharmaceutical Science, 2010, Volume

3, Issue 2, page. 24-32

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